1. Field of the Invention
The present invention concerns the fabrication of whispering gallery mode (“WGM”) sensors that can detect the presence of, identify the composition of, and/or measure an amount or concentration of substances (referred to generally as “target entities” or “target analytes”), such as chemical or biological entities, even in amounts as small as a single protein or virus particle. More specifically, the present invention concerns methods and apparatus to selectively functionalize a sensing ribbon on a resonator of a WGM sensor.
2. Background Information
There exists an ongoing need for sensors for detecting various “target entities” such as, for example, infectious agents (e.g., viruses, bacteria, etc.), toxins, small amounts of proteins, DNA, RNA, etc. Similarly, there exists an ongoing need for sensors for measuring DNA hybridization, protein adsorption, biomolecular mass, etc.
One known device used to detect the presence of small particles is a microsphere sensor coupled to an optical waveguide (e.g., an eroded optical fiber), one end of which is optically coupled with a light source and the other end with a light detector. Whispering gallery modes of the light circulating within the microsphere can be observed in optical signals detected at the detector. Target entities selectively captured (e.g., adsorbed) by target receptors on the surface of the microsphere may shift the whispering gallery modes. These so-called WGM sensors have emerged as an important optical tool for detection and analysis of trace quantities of biological materials. These WGM sensors have been employed in a host of applications including the detection of virus and bacteria, measurement of DNA hybridization and protein adsorption, and biomolecular mass determination.
Examples of such WGM sensors are described in U.S. Pat. No. 7,491,491 (referred to as “the '491 patent” and incorporated herein by reference). Although the '491 patent mainly describes microsphere-based WGM sensors, such sensors may employ microresonators (referred to generally as “resonators”) with geometries other than microspheres, such as, for example, (micro-)cylinders, (micro-)rings, (micro-)disks, (micro-)toroids, (micro-)racetracks, (micro-)bottle resonators, and any other geometry capable of supporting WGM. Each of these configurations relies on the inherent sensitivity of the whispering gallery mode resonances within the resonator to changes in the external environment to provide a sensitive detection mechanism.
However, known WGM sensors may have limits on the minimum size of the particles that may be detected and/or identified, or may have challenges associated with their fabrication More specifically, in many WGM sensors, bulk chemical techniques are used to sensitize the resonator surface to the target entity. This can result in variations in the surface sensitivity to binding events, and thus lead to a corresponding variability of the measured signal during the transduction event. To eliminate such variations (which can impact, for example, a size determination of the target entity), it is preferred that the target entities be captured at an optimal sensing region. For example, in spherical micro-resonators, the optimal sensing region of the surface corresponds to the equatorial perimeter about which the whispering gallery mode is stimulated. However, such localization of target receptors on the resonator surface is not possible with traditional bulk chemistry approaches.
U.S. Patent Application Publication No. 2004-0137478 (referred to as “the '478 publication” and incorporated herein by reference), titled “ENHANCING THE SENSITIVITY OF A MICROSPHERE SENSOR,” discusses increasing the sensitivity of WGM sensors to the point where an individual protein molecule, virus particle, or other small target entity can be detected and identified. More specifically, the '478 publication espouses using a microsphere specially treated or silanized in the equator region to create a band (e.g., a narrow band) of target receptors such that the target receptors are substantially limited to a highly sensitive region near the equator of the microsphere. The '478 publication discusses fabricating microsphere sensors having target receptors substantially only at a sensitive equator region of a microsphere's surface by (i) selecting a microsphere with properties (refractive index (“RI”) and radius) suited to the intended sensing application, (ii) optically coupling an eroded optical fiber with the microsphere at an equator, (iii) coating the microsphere with a UV reactive binding agent, such as an epoxy, (iv) selectively establishing an equator region with receptor material by immersing the microsphere in a solution with target receptors, (e.g., of selected amines) and irradiating the equator band with UV light coupled into the microsphere through the eroded optical fiber causing a reaction between the target receptors in the solution and the binding agent, (v) washing the resulting sphere, and (vi) establishing the non-equator region as a non-interacting region (e.g., by immersing the microsphere in a solution of mono-secondary amines, irradiating the entire surface with UV light (e.g., from an external lamp) causing a reaction between the mono-secondary amines and any un-reacted binding agent, and washing).
Unfortunately, however, the fabrication technique discussed in the '478 publication has not worked well in practice. For example, in the approach described in the '478 publication, a UV light source must be made to propagate through the optical waveguide to couple evanescently with the microresonator in order to prepare the device for surface modification. The waveguide employed might be the same in which the sensing laser would propagate However, this is impractical because most optical waveguides are extremely lossy in the ultraviolet spectral region and the sensitizing laser used in fabrication would suffer significant absorption prior to reaching the microresonator. Furthermore, an optical waveguide that is single mode for the sensing laser would inherently be multimode for the UV laser. Such multimode operation is undesirable. In addition, the UV light source would stimulate different modes than those that would be used during the sensing mode of operation. Finally, the UV laser will not produce a strong “light force” pulling the target receptors to the preferred region during fabrication.
In light of the above discussion, it is clear that there is a need to provide improved WGM sensors, as well as improved techniques for fabricating such WGM sensors.